Diabetes is a disorder characterized by impaired glucose metabolism manifested by an elevated glucose level in subjects. There are two forms of diabetes based on the underlying defects of the disease. Type I diabetes arises when subjects lack pancreatic β-cells producing insulin, the hormone that regulates glucose utilization. Type II diabetes arises when subjects have impaired β-cell function, including other abnormalities. In type II diabetic subjects, plasma insulin levels may be the same or even elevated compared to non-diabetic subjects. Such plasma insulin levels, while elevated, lead to impaired insulin-stimulated glucose uptake in muscles. Also, insulin-resistant adipocytes have diminished capacity to mobilize lipids and triglycerides. Consequently, an increase in circulating glucose and lipids is seen, leading to the metabolic abnormalities often associated with type II diabetes.
Type I subjects are currently treated with insulin. While the majority of type II subjects are treated with sulfonylureas or metformin, these subjects gradually lose the ability to respond to monotherapy, thus requiring treatment with multiple drugs.
An option for normalizing blood glucose levels is the use of combination therapies. For example, an FDA approved combination treatment of type II diabetes is the use of dipeptidyl peptidase-IV (DPP-IV) inhibitors with metformin. Another combination treatment currently under investigation uses glucokinase (“GK”) activators in combination with metformin and is described in WO11/149945.
The long-term efficacy of therapies for type II diabetes is limited by the risk of developing side effects, for example, hypoglycemia and weight gain in subjects undergoing treatment. Accordingly, there is a need to find better options for treating type II diabetes, which include restoring insulin sensitivity and/or controlling weight gain in subjects undergoing such treatment.